30 Oct 2018

Cortese S, Coghill D. Evid Based Ment Health 2018; 21: 173-176

Over the past 20 years, there has been a significant increase in the body of research on ADHD. This may be due to a number of factors, including increased awareness of the impact of ADHD, technological and methodological advances, as well as increased pharmaceutical company interest. In this selective review,* the authors examined what they considered to be the most important advances in ADHD research during this period.

Changes to diagnostic criteria

The publication of the Diagnostic and Statistical Manual of Mental Disorders – 5th Edition (DSM-5™) in 2013 introduced significant changes to the diagnostic criteria for ADHD:

Changes in the threshold for ADHD symptoms and age of onset: in older adolescents and adults, the number of symptoms necessary for an ADHD diagnosis was reduced from 6 to 5. Additionally, the required age of onset was changed from ‘prior to 7’ to ‘prior to 12’. The authors emphasised that although the purpose of these changes was well intended, they are limited by a lack of empirical evidence. Furthermore, more focus should be placed on precisely defining functional impairment rather than the number of symptoms.

Dual diagnosis of ADHD and autism spectrum disorders (ASD): until the publication of the DSM-5™, the diagnosis of ADHD was excluded in the presence of ASD; this change in guidelines was supported by a significant body of empirical evidence.

‘Subtypes’ of ADHD replaced by ‘presentations’: this change in diagnostic criteria acknowledged the instability in the phenotypic manifestation of inattention or hyperactive/impulsive symptoms, in contrast to the more ‘static’ notion of a subtype.

Epidemiology

Differences in the prevalence of ADHD have been reported between countries (Faraone et al. 2003), with differential rates of diagnosis in North America and Europe (Taylor et al. 1984). These findings suggest that ADHD may be more a social construct than a ‘real’ disorder, which has attracted considerable controversy and further investigation over the past two decades. A meta-analysis published in 2007 found that a number of diagnostic variables, including diagnostic criteria, source of information, requirement of impairment for diagnosis, and geographical region, had a significant impact on the estimated pooled rate of ADHD (5.29%). In fact, a significant difference in prevalence only emerged between North America and both Africa and the Middle East, with no difference reported between North America and Europe (Polanczyk et al. 2007). Another recent meta-analysis found no evidence to support an increase in the epidemiological prevalence of ADHD over the past 30 years when standardised diagnostic procedures were followed (Polanczyk et al. 2014). The authors stated that these results suggest the trend for increased rates of ADHD diagnosis may be explained by cultural and social factors, rather than actual increases in prevalence of the disorder.

The majority of the epidemiological studies performed to date focus on school-aged children from North America and Europe; therefore, the authors emphasised the need for further population-based studies from other continents and different age groups. In the authors’ opinion, longitudinal studies aimed at better understanding predictors of remission and persistence of ADHD in adulthood, as well as development of standardised definitions of remission and persistence, are needed to derive conclusive findings from the current body of evidence.

Genetic and environmental causes of ADHD

Significant advances in technology have led to the emergence of novel approaches to identify the genes underpinning the high heritability of ADHD. However, these efforts have perhaps been more challenging than originally anticipated, largely due to the complex genetic and environmental aetiology of ADHD:

Candidate gene approach: aims to identify variant genes involved in the pathophysiology of ADHD; however, to date, the approach has only identified 10 genes as having a significant role.

Genome-wide association studies: allow the analysis of a large number of common single-nucleotide polymorphisms across the entire genome. Initial efforts were unsuccessful, but a recent breakthrough led to the identification of 12 independent loci.

Copy number variants (CNVs): defined as replications or deletions of DNA with a length of at least 1kb. Although CNVs over-represented in ADHD have been identified, studies suggest that their contribution can only explain 0.2% of ADHD heritability.

Environmental factors: considerable data suggest that prenatal and postnatal factors, including maternal smoking and alcohol use, low birth weight, premature birth and exposure to environmental toxins, are associated with increased risk of ADHD. However, apart from preterm birth, genetic studies have implicated a number of confounding familial factors, which do not support a causal role of environmental factors.

The authors expressed the opinion that more research is needed to better understand the interplay between environmental factors and genes. Despite this, genetic research thus far has the potential to pave the way for promising areas of research, including the use of pluripotent stem cells to model brain circuits and the use of zebrafish and fruit fly models to replace currently available animal models of ADHD.

Neuroimaging

Pathophysiological models of ADHD have changed considerably over the past two decades, with a major paradigm shift from alterations in a limited number of individual brain regions to dysfunction in larger brain networks:

Structural magnetic resonance imaging (MRI) studies: meta-analyses and mega-analyses have consistently reported alterations in the basal ganglia, as well as a number of other subcortical areas.

Functional MRI studies: a comprehensive meta-analysis demonstrated that the majority of ADHD-related hypoactivated areas fell within the ventral attention and frontoparietal networks. Conversely, hyperactivated areas were related to the default mode network or visual network. These findings are in line with the default mode network hypothesis of ADHD, which the authors described as one of the most inspiring proposals in the neuroscience of ADHD over the past two decades.

Although studies have gained further insight into the brain networks that are dysfunctional in ADHD, the authors stated that they look forward to the next generation of neuroimaging studies, which bring promise of translating these findings into clinical practice.

Treatment

Over the past two decades, there has been a marked increase in the number of randomised controlled trials (RCTs) aimed at testing the short-term efficacy and tolerability of pharmacological treatments for ADHD. Additionally, several lines of research into non-pharmacological interventions have also been developed:

Pharmacological interventions: a comprehensive network meta-analysis of 133 RCTs was conducted to investigate the efficacy and safety of different medications compared with placebo. Evidence from this meta-analysis supported methylphenidate as the preferred first-choice medication for the short-term treatment of ADHD in children/adolescents, and amfetamines for adults (Cortese et al. 2018).

Non-pharmacological interventions: the European ADHD Guidelines Group has conducted a series of meta-analyses to investigate the role of non-pharmacological interventions in ADHD treatment. Overall, results from these meta-analyses suggest that some interventions, including behavioural intervention or cognitive training, may be effective to reduce associated ADHD impairments. Additionally, some dietary interventions, including fatty acid supplementation and exclusion of artificial food colours, are only associated with a small effect size (Sonuga-Barke et al. 2013). Considering the current body of research, the authors suggest that further evidence is needed to recommend the routine use of non-pharmacological interventions as highly effective treatment for ADHD core symptoms. Despite this, behavioural interventions and cognitive training may be effective for important ADHD-associated impairments.

In the future, the authors noted that it will be important to further evaluate the long-term efficacy and safety of treatments using RCTs with withdrawn designs, as well as additional population-based studies with self-controlled methodologies and longitudinal follow-up studies.

Future directions

The authors concluded that the multiple scientific advances over the past 20 years have successfully answered many questions in the ADHD field. Despite this, many questions remain unanswered. Strengthening multidisciplinary collaborations, utilising large data sets in the spirit of Open Science and the support of research activities in less-advantaged countries will be key in facing these challenges.

*This selective review relied mostly on meta-analyses, retrieved with a search in PubMed using the following syntax/terms (update: 8 August 2018): (ADHD OR Attention Deficit OR Hyperkinetic Disorder) AND (meta-analy* or metaanaly)

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